I. Field of the Invention
The present invention relates generally to the fields of molecular biology and oncology. More particularly, it concerns diagnostic, prognostic, and therapeutic methods and compositions involving ErbB2-overexpressing cancers and potential efficacy of ErbB2 targeting agents to treat such cancers. The invention involves evaluating PTEN expression and/or activity to evaluate and/or predict efficacy or possible resistance to such agents.
II. Description of Related Art
Overexpression of ErbB2, a 185 kDa membrane receptor tyrosine kinase, is found in approximately 20-30% of human breast cancers and many other cancer types (Slamon et al., 1987; Yu and Hung, 2000). ErbB2 overexpression leads to a very aggressive cancer phenotype and poor patient survival (Yu and Hung, 2000). Numerous efforts have been directed at developing ErbB2-targeting cancer therapies (Bange et al., 2001). One successful example is the recombinant humanized anti-ErbB2 monoclonal antibody trastuzumab (Herceptin) that specifically binds to the extracellular domain of ErbB2 (Shepard et al., 1991). The currently known mechanisms underlying trastuzumab's anti-tumor activity include the down-regulation of p185ErbB2 and the subsequent inhibition of its down-stream PI3K-Akt signaling pathway (Hudziak et al., 1989; Yakes et al., 2002), the induction of G1 arrest and cyclin-dependent kinase inhibitor p27kip1 (Sliwkowski et al., 1999), and the inhibition of ErbB2 ectodomain cleavage (Molina et al., 2001). Despite these and other reported functions resulting from ErbB2 down-regulation (Petit et al., 1997), the mechanism of trastuzumab's anti-tumor activity remains a fundamental question to be clearly addressed (Albanell and Baselga, 2001).
As the first FDA approved therapeutic antibody for metastatic breast cancer, trastuzumab has demonstrated durable responses as a single agent and striking therapeutic efficacy in combination with other chemotherapeutics (Baselga et al., 1996; Cobleigh et al., 1999; Esteva et al., 2002; Pegram et al., 1998; Seidman et al., 2001; Slamon et al., 2001; Vogel et al., 2002). However, only less than 35% of patients with ErbB2-overexpressing metastatic breast cancer respond to trastuzumab as a single agent whereas ˜5% patients suffer from severe side effects (e.g., cardiac dysfunction) and 40% of patients experience other adverse effects from trastuzumab treatment (Cobleigh et al., 1999; Vogel et al., 2002). Thus, there is an urgent need to identify patients who are unlikely to respond to trastuzumab treatment to spare them the potential side effects and unnecessary cost. More importantly, trastuzumab resistance-conferring factors may serve as molecular targets for overcoming trastuzumab resistance. Unfortunately, there is very limited information on mechanisms of trastuzumab resistance of breast cancer cells. Currently, there is no clinically verified factor that can be used to predict trastuzumab resistance (Albanell and Baselga, 2001).
Consequently, there is a need for a screen to evaluate whether a patient may be resistant to trastuzumab in order to prevent unnecessary side effects and costs in breast cancer patients who might otherwise receive the treatment even though they are resistant. Methods and kits for determining whether a patient might have resistance or susceptibility to an ErbB2-overexpressing cancer have not been previously known.